Strategic Therapeutic Targeting to Overcome Venetoclax Resistance in Aggressive B-cell Lymphomas

Abstract

B-cell lymphoma-2 (BCL-2), an antiapoptotic protein often dysregulated in B-cell lymphomas, promotes cell survival and provides protection from stress. A recent phase I first-in-human study of the BCL-2 inhibitor venetoclax in non-Hodgkin lymphoma showed an overall response rate of 44%. These promising clinical results prompted our examination of the biological effects and mechanism of action underlying venetoclax activity in aggressive B-cell lymphoma, including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). MCL and DLBCL cell lines, primary patient samples, and patient-derived xenograft (PDX) models were utilized to examine venetoclax efficacy. Furthermore, the mechanisms underlying venetoclax response and the development of venetoclax resistance were evaluated using proteomics analysis and Western blotting. Potential biomarkers linked to venetoclax activity and targeted combination therapies that can augment venetoclax response were identified. We demonstrate that DLBCL and MCL cell lines, primary patient samples, and PDX mouse models expressing high BCL-2 levels are extremely sensitive to venetoclax treatment. Proteomics studies showed that venetoclax substantially alters the expression levels and phosphorylation status of key proteins involved in cellular processes, including the DNA damage response, cell metabolism, cell growth/survival, and apoptosis. Short- and long-term exposure to venetoclax inhibited PTEN expression, leading to enhanced AKT pathway activation and concomitant susceptibility to PI3K/AKT inhibition. Intrinsic venetoclax-resistant cells possess high AKT activation and are highly sensitive to PI3K/AKT inhibition. These findings demonstrate the on-target effect of venetoclax and offer potential mechanisms to overcome acquired and intrinsic venetoclax resistance through PI3K/AKT inhibition. .

The HDAC and PI3K dual inhibitor CUDC-907 synergistically enhances the antileukemic activity of venetoclax in preclinical models of acute myeloid leukemia

“…6 Pham and colleagues recently reported that venetoclax treatment activates the DNA damage response in lymphoma cells, though the mechanism is unknown. 28 In agreement, we show that inhibition of Wee1 or RRM1 in combination with venetoclax cooperatively induce DNA damage in AML cells.…”

Overcoming ibrutinib resistance by targeting phosphatidylinositol-3-kinase signaling in diffuse large B-cell lymphoma

“…As an example, one study showed that either short-or long-term exposure of B-cell lymphoma cell lines (MCL and DLBCL) to venetoclax led to the development of venetoclax resistance due to a reduction in PTEN expression (a negative regulator of the PI3K/AKT activation pathway). 36 Our RPPA analysis from three IR cell lines showed a significant decrease in PTEN expression with enhanced expression of activated AKT (p-AKT) and downstream activation of mTOR signaling, suggesting the critical role of PI3K signaling in survival of acquired IR-DLBCLs ( Figure 2C).…”

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

“…Our group has been involved in various clinical trials with ibrutinib, acalabrutinib, venetoclax (a Bcl2 inhibitor), and their combinations with anti‐CD20 monoclonal antibodies (mAb), rituximab, or with obinutuzumab. Furthermore, we are characterizing ibrutinib, acalabrutinib, and venetoclax‐refractory MCL and championing the CAR‐T cell clinical trials (Zuma‐2) in MCL in the United States.…”